Inhibition of p38 Mitogen-activated Protein Kinase Impairs Influenza Virus-induced Primary and Secondary Host Gene Responses and Protects Mice from Lethal H5N1 Infection

Börgeling, Yvonne; Schmolke, Mirco; Viemann, Dorothee; Nordhoff, Carolin; Roth, Johannes; Ludwig, Stephan

doi:10.1074/jbc.m113.469239

Cited by 110 publications

(109 citation statements)

References 50 publications

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“…Our results indicate that upregulation of the Irf3 -and Irf7 -independent pathways, namely the JNK pathway, and the resulting higher infiltration of granulocytes may be an important driver of a severe outcome. This result is in line with the findings of Börgeling et al [43] , who presented p38 MAPK as a potential target for antiviral strategies since an inhibitor was able to protect mice from lethal influenza.…”

Section: Irf7supporting

confidence: 91%

Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Hatesuer

Hoang

Riese³

et al. 2016

J Innate Immun

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The interferon (IFN) pathway plays an essential role in the innate immune response following viral infections and subsequent shaping of adaptive immunity. Infections with influenza A viruses (IAV) activate the IFN pathway after the recognition of pathogen-specific molecular patterns by respective pattern recognition receptors. The IFN regulatory factors IRF3 and IRF7 are key players in the regulation of type I and III IFN genes. In this study, we analyzed the role of IRF3 and IRF7 for the host response to IAV infections in Irf3^-/-, Irf7^-/-, and Irf3^-/-Irf7^-/- knockout mice. While the absence of IRF3 had only a moderate impact on IFN expression, deletion of IRF7 completely abolished IFNα production after infection. In contrast, lack of both IRF3 and IRF7 resulted in the absence of both IFNα and IFNβ after IAV infection. In addition, IAV infection of double knockout mice resulted in a strong increase of mortality associated with a massive influx of granulocytes in the lung and reduced activation of the adaptive immune response.

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Section: Irf7supporting

confidence: 91%

Deletion of Irf3 and Irf7 Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Hatesuer

Hoang

Riese³

et al. 2016

J Innate Immun

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“…JNK is a signal transducer to maintain a prosurvival state or the expression of a proinflammatory response as well as apoptotic signals (12). Despite its importance in the replication of many viruses (15)(16)(17)(18), MAPK signaling in the context of alphavirus infections has been only sparsely investigated. Only the activation of ERK in CHIKVinfected mouse astrocytes (19) and in SINV-infected human endothelial cells (20) has been described thus far.…”

mentioning

confidence: 99%

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Varghese

Thaa

Amrun

et al. 2016

J Virol

120

103

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Chikungunya virus (CHIKV) has infected millions of people in the tropical and subtropical regions since its reemergence in the last decade. We recently identified the nontoxic plant alkaloid berberine as an antiviral substance against CHIKV in a highthroughput screen. Here, we show that berberine is effective in multiple cell types against a variety of CHIKV strains, also at a high multiplicity of infection, consolidating the potential of berberine as an antiviral drug. We excluded any effect of this compound on virus entry or on the activity of the viral replicase. A human phosphokinase array revealed that CHIKV infection specifically activated the major mitogen-activated protein kinase (MAPK) signaling pathways extracellular signal-related kinase (ERK), p38 and c-Jun NH 2 -terminal kinase (JNK). Upon treatment with berberine, this virus-induced MAPK activation was markedly reduced. Subsequent analyses with specific inhibitors of these kinases indicated that the ERK and JNK signaling cascades are important for the generation of progeny virions. In contrast to specific MAPK inhibitors, berberine lowered virus-induced activation of all major MAPK pathways and resulted in a stronger reduction in viral titers. Further, we assessed the in vivo efficacy of berberine in a mouse model and measured a significant reduction of CHIKV-induced inflammatory disease. In summary, we demonstrate the efficacy of berberine as a drug against CHIKV and highlight the importance of the MAPK signaling pathways in the alphavirus infectious cycle. IMPORTANCEChikungunya virus (CHIKV) is a mosquito-borne virus that causes severe and persistent muscle and joint pain and has recently spread to the Americas. No licensed drug exists to counter this virus. In this study, we report that the alkaloid berberine is antiviral against different CHIKV strains and in multiple human cell lines. We demonstrate that berberine collectively reduced the virus-induced activation of cellular mitogen-activated protein kinase signaling. The relevance of these signaling cascades in the viral life cycle was emphasized by specific inhibitors of these kinase pathways, which decreased the production of progeny virions. Berberine significantly reduced CHIKV-induced inflammatory disease in a mouse model, demonstrating efficacy of the drug in vivo. Overall, this work makes a strong case for pursuing berberine as a potential anti-CHIKV therapeutic compound and for exploring the MAPK signaling pathways as antiviral targets against alphavirus infections. C hikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease spread by Aedes mosquitoes and characterized by a sudden onset of febrile illness, nausea, headache, and most importantly, severe and persistent musculoskeletal pain (1). It reemerged in tropical Asia and Africa 1 decade ago and since 2013 has infected more than 1.5 million people in the Americas (2). So far, no licensed vaccine or antiviral treatment exists to counter this disease. Over the years, many research groups have focused on...

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“…During sepsis, bacterial ligands such as LPS engage TLRs and activate proinflammatory signaling, resulting in the activation of transcription factors NF-kB and AP-1 (12,30,32). Our results show that intraperitoneal LPS robustly activates IKK-b and MAPK (p38 and JNK) phosphorylation in the developing lung, and NOX2 deficiency inhibits canonical TLR pathway signaling.…”

Section: Expression Was Attenuated In Nox2mentioning

confidence: 67%

“…p38 and JNK phosphorylation induced by systemic LPS were decreased in the lungs of NOX2 2/2 mice. To examine the role of p38 in enhancing NF-kB signaling in our model, we performed additional experiments with the specific p38 inhibitor (p38-I, SB202190, 10 mg/kg) (29,30). Pretreatment with p38-I (2 hr) decreased LPS-induced p38 (Thr 180 /Tyr 182 ) phosphorylation, NF-kB activation.…”

Section: Nox2 Regulates Pulmonary Tlr Pathway Activation In Sepsismentioning

confidence: 99%

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

Buonfiglio

Bagegni

Borcherding

et al. 2016

Am J Respir Cell Mol Biol

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In premature infants, sepsis is associated with alveolar simplification manifesting as bronchopulmonary dysplasia. The redox-dependent mechanisms underlying sepsis-induced inflammation and alveolar remodeling in the immature lung remain unclear. We developed a neonatal mouse model of sepsisinduced lung injury to investigate whether nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) regulates Toll-like receptor (TLR)-mediated inflammation and alveolar remodeling. Six-day-old NOX2 1/1 and NOX2 2/2 mice were injected with intraperitoneal LPS to induce sepsis. Lung inflammation and canonical TLR signaling were assessed 24 hours after LPS. Alveolar development was examined in 15-day-old mice after LPS on Day 6. The in vivo efficacy of a NOX2 inhibitor (NOX2-I) on NOX2 complex assembly and sepsis-induced lung inflammation were examined. Lung cytokine expression and neutrophil influx induced with sepsis in NOX2 1/1 mice was decreased by .50% in NOX2 2/2 mice. LPS-induced TLR4 signaling evident by inhibitor of NF-kB kinase-b and mitogen-activated protein kinase phosphorylation, and nuclear factor-kB/AP-1 translocation were attenuated in NOX2 2/2 mice. LPS increased matrix metalloproteinase 9 while decreasing elastin and keratinocyte growth factor levels in NOX21/1 mice. An LPS-induced increase in matrix metalloproteinase 9 and decrease in fibroblast growth factor 7 and elastin were not evident in NOX22/2 mice. An LPS-induced reduction in radial alveolar counts and increased mean linear intercepts were attenuated in NOX2 2/2 mice. LPS-induced NOX2 assembly evident by p67phox/gp91phox coimmunoprecipitation was disrupted with NOX2-I. NOX2-I also mitigated LPS-induced cytokine expression, TLR pathway signaling, and alveolar simplification. In a mouse model of neonatal sepsis, NOX2 regulates proinflammatory TLR signaling and alveolar remodeling induced by a single dose of LPS. Our results provide mechanistic insight into the regulation of sepsis-induced alveolar remodeling in the developing lung.Keywords: nicotinamide adenine dinucleotide phosphate oxidase; sepsis; Toll-like receptor signaling; neonatal lung injury; bronchopulmonary dysplasia Postnatal inflammation and tissue injury in the developing lung contribute to the disrupted alveolar development observed in premature infants with bronchopulmonary dysplasia (BPD) (1, 2). Risk factors associated with BPD, such as hyperoxia, barotrauma, and sepsis, trigger the production of reactive oxygen species (ROS) in the premature lung, which contributes to lung inflammation and matrix degradation (3-5). Multiple investigators have shown that markers of oxidant-mediated lung injury, such as 8-Oxo-29-deoxyguanosine, oxidized surfactant phospholipids, F2-isoprostanes, and nitrotyrosine, are elevated in the bronchoalveolar lavage, serum, or urine of premature infants who subsequently develop BPD (4-7). Therapies to mitigate oxidant stress, such as recombinant superoxide dismutase and vitamin A, have been used in premature infants to decrease BPD, with limited succes...

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Inhibition of p38 Mitogen-activated Protein Kinase Impairs Influenza Virus-induced Primary and Secondary Host Gene Responses and Protects Mice from Lethal H5N1 Infection

Cited by 110 publications

References 50 publications

Deletion of <b><i>Irf3</i></b> and <b><i>Irf7</i></b> Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

Deletion of <b><i>Irf3</i></b> and <b><i>Irf7</i></b> Genes in Mice Results in Altered Interferon Pathway Activation and Granulocyte-Dominated Inflammatory Responses to Influenza A Infection

The Antiviral Alkaloid Berberine Reduces Chikungunya Virus-Induced Mitogen-Activated Protein Kinase Signaling

Protein Kinase Cζ Inhibitor Promotes Resolution of Bleomycin-Induced Acute Lung Injury

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